This invention relates to the fields of pharmaceutical chemistry and synthetic organic chemistry. Specifically, the invention is an improved process for the synthesis of duloxetine,(S)-(+)N-methyl-3(1-naphthalenyloxy)-3-(2-thienyl)propanamine. Compounds of Formula I:
wherein R is methyl or hydrogen are intermediates useful in the synthesis of duloxetine. Duloxetine hydrochloride is a pharmaceutical currently marketed in the United States as an anti-depressant and inhibits the uptake of both norepinephrine and serotonin. Duloxetine is disclosed in U.S. Pat. Nos. 5,023,269 and 4,956,388 by Robertson, et al. The synthesis of duloxetine is discussed in more detail by Berglund, R. A., Org. Proc. Res. Devel., 1, 328 (1997) and Deeter, et al., in Tetrahedron Letters, 31(40), 7101-04 (1990) and aspects patented in U.S. Pat. Nos. 5,362,866 and 5,491,243.
Additional synthetic schemes and processes are reported for conversion to duloxetine. Several of these syntheses proceed via a monomethylaminoalcohol (Compound Ia in Scheme 1 below). As shown in Scheme 1, Compound Ia is arylated with 1-fluoronaphthalene to give Compound A, which, is duloxetine.

U.S. Pat. No. 5,362,866 discloses a process to synthesize duloxetine via arylation of a dimethylamino alcohol, Compound Ib. In Scheme 2 below, Compound Ib is arylated with 1-fluoronaphthalene to give Compound B, which may be recovered as the phosphoric acid salt if desired. The dealkylation of Compound B yields duloxetine as a final product.

To date most processes utilized to synthesize duloxetine proceed via an arylation step involving sodium hydride. Sodium hydride is a strong base that can pose environmental and safety hazards which are exacerbated upon manufacturing scale-up. Known processes to synthesize duloxetine also utilize DMSO. DMSO can form dimsyl anion when coupled with sodium hydride. It is reported that dimsyl anion can cause racemization, which poses difficulty as only one enantiomer, (S)-duloxetine hydrochloride, is the desired product. Moreover, thermochemical hazards are associated with the degradation of dimsyl anion. Therefore, an improved process that avoids the use of sodium hydride and generation of dimsyl anion is needed.
Use of DMSO alone as a solvent in the present invention results in complete racemization. Further, use of DMSO in a large scale manufacturing process is associated with increased cost of recovery, or of incineration. DMSO is also associated with SOx emissions, posing an additional environmental concern. An improved process that utilizes less DMSO is needed.
International Patent Application Publication WO 2004/056795, published Jul. 8, 2004, discloses a process for the synthesis of duloxetine utilizing a weaker base than sodium hydride but still utilizing DMSO. However, the process described in WO 2004/056795 describes the use of a phase transfer catalyst to prevent racemization. The toxicity of phase transfer catalysts such as 18-crown-6 has been reported. See Takayama, K. et al, Chem. Pharm. Bull. 25(11), 3125 (1977), and Hendrixson, R. et. al, Toxicol. Appl. Pharmacol., 44, 263 (1978). International Patent Application Publication WO 00/61540, published Oct. 19, 2000, describes arylation of 3-hydroxy-3-arylpropylamines. However, the process described therein requires the use of either 1,3-dimethyl-2-imidazolidinone or N-methylpyrrolidinone.
Significant or complete racemization is observed at known conditions when using potassium hydroxide for the arylation of Compounds of Formula I in DMSO with 1-fluoronaphthalene. Surprisingly, almost no racemization is observed when Compounds of Formula I are arylated via the process of the instant invention. Further, a surprising correlation was discovered between suitable solvent system parameters and amount of racemization observed. The process of the present invention effects arylation of Compounds of Formula I with 1-fluoronaphthalene utilizing potassium hydroxide and particular organic solvents, such as glymes or mixtures of DMSO and toluene. The present invention provides improved reaction conditions for this arylation whereby chiral integrity, purity, and yield are preserved, dimsyl anion is not formed, a phase transfer catalyst is not required, and numerous safety and environmental improvements observed by removal of the requirement of sodium hydride and utilizing less DMSO.